Ibandronate sodium is one of the most potent antiresorptive drugs that directly inhibit osteoclast activity and present an effective pharmacologic alternative for controlling hypercalcemia. Ibandronate sodium binds to hydroxyapatite in calcified bone, rendering it resistant to hydrolytic dissolution by phosphatases, thereby inhibiting both normal and abnormal bone resorption. This drug increases bone mass and decreases the risk of fractures and is therefore particularly well adapted to bone and calcium metabolic diseases such as for instance osteoporosis or Paget's disease (EP-A 0252504).
For the preparation of bisphosphonic acids the following processes are known in the state of the art and have been considered.
EP 0402152 discloses the preparation of crystalline 4-amino-1-hydroxybutyllidene-1-bisphosphonic acid monosodium trihydrate, carried out in one step in presence of phosphorus trihalide, phosphorous acid and methane sulfonic acid. This process allows the reaction mixture to remain fluid.
WO 03/097655 discloses the preparation of a bisphosphonic acid including the step of combining a carboxylic acid with phosphorous acid and phosphoryl chloride in the presence of a diluent. The diluent includes aromatic hydrocarbons such as toluene, xylene and benzene or inert silicone fluids such as polydimethylsiloxane and polymethylphenylsiloxane.
However, the methods described in the art are not satisfactory with regard to yield and purity, in particular with respect to the synthesis of ibandronate sodium.